Thesis (Ph. D.)--State University of New York at Binghamton, Department of Psychology, 2009. / Includes bibliographical references.

Thesis (Ph.D.)--University of Wollongong, 2005. / Typescript. Includes bibliographical references: leaf 288-310.

Accelerated long-term forgetting (ALF) is a recently described memory impairment associated with epilepsy. Patients with ALF appear to learn and initially retain new information normally, but forget it at an accelerated rate over subsequent days. ALF can have a profound impact on the lives of the people who suffer from it, but it is also of theoretical interest. In particular, the study of this disorder may provide insight into the mechanisms of memory consolidation. ALF is especially prevalent in transient epileptic amnesia (TEA), an epileptic syndrome in which the seizure focus is thought to be the medial temporal lobes (MTL). The MTL house the hippocampus and a number of other structures critical for declarative memory function. The aims of this doctoral thesis were to investigate which aspects of memory function are disrupted in patients with TEA-associated ALF, and to shed light on the neural basis of the memory impairment. Slow wave sleep (i.e. deep sleep) is known to exacerbate epileptic activity. It is also thought to play a key role in the consolidation of declarative memory. The most commonly posited explanation of ALF is the disruption of sleep- dependent memory consolidation. However, it remains possible that ALF is caused by a subtle problem with encoding that usually goes undetected until delayed memory tests. The results of this thesis demonstrate that sleep can actually benefit memory retention in TEA ALF patients just as much as it does in healthy people, and that it is not necessary for the retention interval to contain sleep in order for ALF to be seen. However, the relationship between slow wave sleep and memory was found to be abnormal in these patients. The amount of slow wave sleep, and the power in the slow oscillation frequency range, during the post-learning night correlated negatively with the benefit of that night of sleep for memory retention. Furthermore, resting-state brain activity patterns thought to reflect post-encoding memory reprocessing were found to correlate negatively with subsequent memory performance in these patients. Another chapter of this thesis provides evidence that TEA ALF patients encode memories abnormally; these patients showed reduced activity in the left hippocampus while viewing stimuli that they went on to forget. Furthermore, this encoding-related brain activity correlated with their long-term forgetting. The final experimental chapter reports a correlation in these patients between grey matter in the left hippocampus and long-term forgetting, which cannot entirely account for the encoding-related brain activity results. The hippocampus and its surrounding structures are thought to be critical to our ability to discriminate between similar stimuli and events. An intriguing hypothesis consistent with the pattern of results in this thesis is that ALF is caused by a functional impairment of the MTL that results in a diminished capacity to distinguish between similar experiences, ultimately causing memory problems; abnormally formed memories may interact with new material and memory consolidation processes in an aberrant manner, leading to retrieval deficits.

Catechol-O-methyltransferase (COMT) metabolises catechol-containing compounds, including dopamine. The aim of this thesis was to investigate whether COMT is involved in hippocampal function. This thesis also explored the role of functional polymorphisms within the COMT gene in the pathogenesis of schizophrenia and schizophrenia-related phenotypes. First, as part of a study investigating the role of COMT in schizophrenia, human hippocampal COMT mRNA levels were shown to be neither altered in schizophrenia or bipolar disease, nor affected by COMT genotype. Hence, functional COMT polymorphisms do not appear to operate by altering gross COMT mRNA expression. Importantly, this study showed that COMT is expressed in the human hippocampus. Second, the role of COMT in hippocampal neurochemistry was explored by studying the effect of pharmacological COMT inhibition on catecholamines and metabolites in rat hippocampal homogenates, and extracellularly, using microdialysis. Both demonstrated that COMT modulates hippocampal dopamine metabolism. Thus, hippocampal COMT is of functional significance with respect to dopamine. Third, the effect of COMT inhibition on hippocampus-dependent behaviour was investigated. The results suggested a memory-enhancing effect of pharmacological COMT inhibition on hippocampus-dependent associative and non-associative forms of short-term memory in rats. In contrast, acute COMT inhibition appeared to have no effect on behavioural correlates of ventral hippocampal function i.e. anxiety-like behaviour. In summary, the expression of COMT mRNA in the human hippocampus, as well as the effect of COMT inhibition on rat hippocampal neurochemistry and hippocampus-dependent behaviour provide evidence for a functional role of COMT in the hippocampus. Moreover, changes in COMT activity alter hippocampal dopamine metabolism, which could be a potential mechanism for the role of COMT in hippocampus-dependent short-term memory.